1. Technical Field
This invention relates to a novel antitumor agent and an antitumor action controlling agent. More particularly, the present invention relates to a novel antitumor agent comprising (a) a compound having antitumor action and (b) a growth factor, a peptide corresponding to a part of its constituent (fragment), a derivative of these or a salt of these (hereinafter sometimes called "growth factor, etc.") as the active ingredients, and also to a novel antitumor action controlling agent comprising a growth factor, a peptide corresponding to a part of its constituent (fragment), a derivative of these or a salt of these.
2. Prior Art
A growth factor is "a substance which promotes growth of animal cells in vivo or in vitro but is not a neutrient substance" [Ann. Rev. Biochem., 45, 531-558 (1976)], and, accordingly, hormones or carriers thereof known in the art also fall within the category of a growth factor.
At present, about 40 species of such factors have been known. Those growth factors may include, for example, those classified into the insulin family [insulin, insulin-like growth factors (IGF-I, IGF-II, etc.), mammary stimulating factor (MSF), nerve growth factor (NGF), etc.]; those classified into the epidermal growth factor family [epidermal growth factor (EGF), transforming growth factors (TGF.sub..alpha., TGF.sub..beta., TGF.sub..gamma.), etc.]; those classified into the platelet-derived growth factor family [platelet-derived growth factor (PDGF), osteosarcoma-derived growth factor (ODGF), fibroblast growth factor (FGF), etc.]; and others [colony stimulating factor (CSF), T-cell growth factor, tumor angiogenesis factor (TAF), DNA synthesis promoting factor (DSF), tumor-derived growth factors, fibroblast-derived growth factor (FDGF), etc.]
Epidermal growth factor has been found in mammals. It can be isolated from human and horse urine, and also from rabbit, rat and mouse submaxillary glands. [Adv. Metab. Dis., 8, 265 (1975); and Japanese Laid-open Patent Publication No. 25112/1981]. Among them, human epidermal growth factor (hEGF) was isolated from human urine and introduced as the human-derived factor enhancing both proliferation and keratinization of epidermal tissue by S. Cohen in 1975 [Proc. Natl. Acad. Sci. USA, 72, 1317 (1975)], and it has been known that it is the same substance as the polypeptide reported as human urogastrone (h-UG) which inhibits gastric acid secretion and was isolated from human urine by H. Gregory et al., in the same year [Nature, 257, 235 (1975)]. Human epidermal growth factor/urogastrone has a molecular weight of about 6000, comprising 53 amino acid residues and having three disulfide bonds in its molecule [Metabolism (in Japansese), 17, 51-58 (1980)]. Epidermal growth factor is hereinafter referred to as EGF.
Physiological and pharmacological activities of EGF having been reported include inhibition of gastric acid secretion [Gut, 16, 1877 (1975); ibid, 23, 951 (1982)]; antiulcer action [Gut, 22, 927 (1981); Brit. J. Surg., 64, 830 (1977)]; protection of mucous membrane of digestive canal [Japanese Laid-open Patent Publication No. 9686/1985]; stimulation of DNA synthesis [Gut, 22, 927 (1981); J. Physiol., 325, 35 (1982)]; Enhancement of corneal epithelical regeneration [Exp. Eye Res. 14, 135 (1972)]; stimulation of bone resorption [Endocrinology, 107, 270 (1980)]acceleration of wound healing promoting action [Plast. Riconstr. Surg., 64, 766 (1979); J. Surg. Res., 33, 164 (1982)]; antiinflammatory activity (Japanese Laid-open Patent Publication No. 115784/1985); and analgesic activity (Japanese Laid-open Patent Publication No. 115785/1985), etc.
Some growth factors have been reported to be tumor promoter under limited conditions, in living bodies (hereinafter abbreviated as in vivo). For example, there is such a report on EGF which is one of the active ingredients in the present invention [Surgical Forum 16, 108 (1965); Experientia 32 (7), 913-915 (1976), Science 201, 515-518 (1978); Cancer Res. 39, 239-243 (1979)].
On the other hand, in test tubes, outside the living body (this is hereinafter abbreviated as in vitro), it has been well known that tumor cells having receptors for growth factors are rather inhibited in growth by addition of growth factors, and there is specifically a report that growth of tumor cells having EGF receptors is rather inhibited by addition of EGF [J. Biol. Chem., 259, 7761-7766 (1984); Toxicology Forum, in Japan, 9 (1), 55-62 (1986)]. Also, there is a report that cell growth, although not inhibited, is not enhanced at all by addition of EGF alone [Int. J. Cell Cloning, 3, 407-414 (1985)]. Generally speaking we cannot infer the physiological and pharmacological activities of growth factors in vivo from those in vitro.
Cancer is ranked as almost the first leading cause of death in a lot of countries today. Treatment of cancer is practiced in various ways. The treatment of cancer may include surgery, irradiation, chemotherapy, etc., the former two being local or non-systemic therapy. Since a local therapy can be applied with extreme difficulty when metastasis of the cancer has occurred to other portions than the original lesion, chemotherapy cannot but be relied upon. However, of the antitumor agents used in this method, those having strong antitumor effects have commonly strong adverse effects, and the chemotherapy method can be said to be limited in this respect.
Antitumor agents presently available may include alkylating agents (nitrogen mustard-N-oxide, triethylenemelamine, busulfane, carumustine, dacarbazine, etc.); antimetabolites [methotrexate, 6-mercaptopurine, 5-fluorouracil (5-FU), cytosine arabinoside (Ara-C), cyclocytidine, etc.]; antibiotics [adriamycin (Doxorubicine), actinomycin C, actinomycin D, chromomycin A.sub.3, breomycin, etc.]; vinca alkaloids (vincrystine, demecolcine, etc.); prostaglandins; immunostimulators (polysaccharides such as Picibanil.RTM., Krestin.RTM., etc.); lymphocaines, monocaines (interferons, interleukine-2, etc.); platinum-complexes (cisplatin, etc.); and others.
Thus, there are a large number of antitumor agents which are presently clinically used, but among them specific antitumor agents tend to be used selectively for tumors of specific organs. At present, cancers which can be give 5-year survival by chemotherapy are infantile accute leukemia, Hodgikin's disease, orchioncus, Ewing's tumor, Wilm's tumor, Burkitt's lymphoma, papilloma, and otherwise embryonal rhabdomyosarcomas, skin cancer, ovarian tumor, breast cancer, multiple myeloma, neuroblastoma, etc. However, most of these cancers are relatively rare cancers, and it can be said that no satisfactory antitumor agent has been developed yet against stomach cancer, lung cancer (excluding some species thereof), liver cancer, esophagus cancer, colon cancer, etc., which will more frequently occur (textbook "Tumorology" in Japanese P. 269 (1984), published by Nanzando).
On the other hand, antimetabolites involve a problem different from the above problem. For example, 5-fluorouracil [A Comprehensive Treatise, 5, 327, Prenum Press, Cancer Res., 18, 478 (1958), Gastroenterlogy, 48, 430 (1965), Cancer Treat, Rep., 62, 533 (1987)] which is at present clinically frequently used is one of the antitumor agents having the strongest antitumor action, but it has been reported to have advese effects on digestive truct mucosa, bone marrow, etc. where mitosis of cells occurs abundantly to cause diarrhea or decrease in white blood cells, etc. [Pharmacological Principles of Cancer Treatment, 195 (1982)], and also other antitumor agents as mentioned above are also known to have various adverse effects [textbook "Illustrated Pharmacology", P. 384-385, Asakura Shoten, (1979)]. Thus, antitumor agents of the prior art having strong antitumor actions are generally also strong in their adverse effects. On the other hand, although 1-(2-tetrahydrofulyl)-5-fluorouracil (Tegafur) has relatively little toxicity and side effect, it is said to be slightly inferior in antitumor effect. Thus, those having little side effect are generally weak in their antitumor effects.
Also, a large number of therapies have been practiced for the purpose of potentiating the antitumor effect and preventing the adverse effects by combined use of multiple antitumor agents known in the art. However, no decisive therapeutical method has yet been established.
Further, as a difficulty, when continuous administration of an antitumor agent is practiced, there may sometimes occur a phenomenonthat the tumors acquire resistance to the antitumor agent, whereby the antitumor effect can be obtained with difficulty, This is a problem which is clinically extremely serious and is abruptly increasing in these days. The multiple-agent combined use therapeutical method is an attempt to overcome drug resistance by use of many kinds of antitumor agents with different mechanisms, but it cannot be said that resistance has been overcome, and further toxicity becomes by far heavier than when a single agent is employed.
Further, as to radiation therapy, methods have been developed for improvement of therapeutical results as a part of cancer therapy. Such methods include, for example, a method in which physical dose distribution is improved by irradiation of accelerated heavy ion particles or by a means using .pi. neutrons. However, according to the above method, the accelerator or auxiliary installations, etc., necessary for practicing the method are expensive and also many skilled engineers or physicians are required. Further, radiation therapy is also accompanied with the drawbacks such as great damage to normal tissues, etc.
Accordingly, in order to solve such problems, it has been desired to provide an antitumor agent having strong antitumor action and yet little side effect or an agent controlling antitumor action, and an effective application method of chemotherapy or other cancer therapeutical methods.